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Administrative data

Description of key information

Acute oral toxicity: LD50 > 2200 mg/kg bw (OECD 401 (1987); GLP compliant)

Acute inhalation toxicity: LC50 (rats; 4 hours) > 5.6 mg/L air (actual concentration) (OECD 403 (1981); GLP compliant)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
1987-02-24
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS - Wistar (CHBB:Thom, (SPF))
- Age at study initiation: young adult animals
- Weight at study initiation: males: 175 - 183 g; females: 185 - 192 g
- Fasting period before study: the animals were given no feed at least 16 hours before administration, but water was available ad libitum
- Housing: single housing; stainless steel wire mesh cages, type DK-III (Becker & Co., Castrop-Rauxel, FRG); no bedding in the cages; sawdust in the waste trays
- Diet (ad libitum, except for fasting period as stated above): Kliba-Labordiaet 343, Klingentalmuehle AG, CH-4303 Kaiseraugst, Switzerland
- Water (ad libitum): tap water
- Acclimation period: at least 1 week

ENVIRONMENTAL CONDITIONS - the animals were housed in fully air-conditioned rooms.
- Temperature: range of 20 - 24 °C
- Relative humidity: range of 30 - 70 %
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Based on the physical and chemical characteristics of the test substance no pronounced acute oral toxicity was expected. Therefore a dose of 2200 mg/kg body weight had been chosen for the study.

VEHICLE
- Justification for choice of vehicle: aqueous formulation corresponds to the physiological medium.

MAXIMUM DOSE VOLUME APPLIED: 10.00 mL/kg

DOSAGE PREPARATION: test substance formulation with aqua bidest. (form of administration: suspension); time of day of administration was in the morning
Doses:
2200 mg/kg (concentration 22.000 g/100 mL)
No. of animals per sex per dose:
5 males / 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: individual body weights were determined shortly before application (day 0), weekly thereafter and at the end of the study (before fasting period). Recording of signs and symptoms several times on the day of administration, at least once each workday for the individual animals. A check was made twice each workday and once on saturdays, sundays and on public holidays for general observations and for any dead or moribund animals.
- Necropsy of survivors performed: yes; necropsy at the last day of the observation period. Withdrawal of food at least 16 hours before killing with CO2; then necropsy with gross pathology examination. Necropsy of all animals that died before as early as possible.
Statistics:
not applicable
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 200 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 1% significance level
Mortality:
No mortality occurred.
Clinical signs:
Signs of toxicity have not been noted.
Body weight:
The expected body weight gain has been observed in the course of the study.
Gross pathology:
No abnormalities were noted at necropsy of animals sacrificed at the end of the study.
Interpretation of results:
GHS criteria not met
Conclusions:
LD50 (male and female rats) > 2200 mg/kg bw
According to the EC-Regulation 1272/2008 and subsequent regulations, the test item is not classified as acute toxic via the oral route.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The study fulfils the rquirements for acute oral toxicity under REACH (Regulation (EC) 1907/2006).

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1991-08-08 to 1991-08-22
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Reason for RL- rating: according to Guidance on information requirements and chemical safety assessment Chapter R. 7a: Endpoint specific guidance, inhaled particles should have a MMAD between 1 and 4 microns. The MMAD in this study was slightly above the recommened value.
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
1981-05-12
Deviations:
yes
Remarks:
no vehicle control group was used; no acclimatisation period was stated; it was not stated if a dynamic air flow of 12 to 15 air changes per hour was used; no equilibrium period was stated; clinical observations only at least once on workday
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS - strain: SPF Wistar/Chbb:THOM
- Age at study initiation: approx. 8 - 9 weeks
- Weight at study initiation: males (mean): 284 +/- 4.3 g; females (mean): 203 +/- 8.0 g
- Housing: housed singly in cages type DK III of Becker, without bedding
- Diet (ad libitum during the post exposure period): KLIBA rat/mouse/hamster laboratory diet 24-343-4 10 mm pellets, Klingentalmühle AG, CH-4303 Kaiseraugst, Switzerland
- Water (ad libitum during the post exposure period): drinking water

ENVIRONMENTAL CONDITIONS - the animals were kept in fully air-conditioned rooms
- Temperature: 20 - 24 °C
- Relative humidity: 30 - 70 %
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation: dust
Type of inhalation exposure:
nose/head only
Vehicle:
other: Aerosil and clean air
Mass median aerodynamic diameter (MMAD):
5.1 µm
Geometric standard deviation (GSD):
2.4
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: head-nose inhalation system INA 20 (glass-steel construction, BASF Aktiengesellsschaft, volume V ~55 L): the animals were restrained in tubes and their snouts projected into the inhalation chamber.

- Source and rate of air/method of conditioning air/treatment of exhaust air: the following air flow (supply air) was set: 1,500 L/h
The exposure system was placed in an air-conditioned laboratory.
By means of an exhaust air system the pressure ratios in the inhalation system were adjusted in such a way that the amount of exhaust air was about 10 % lower (excess pressure). This ensured that the mixture of test substance and air was not diluted with laboratory air in the breathing zones of the animals.

- System of generating particulates/aerosols: the aerosol was produced with a dosing -wheel dust generator (Gericke/BASF) and compressed air.
A glass cyclonic separator (BASF) was connected downstream with the generator.
The concentration was adjusted by varying the rotation of the metering disc.

- Method of particle size determination: 30 minutes after the beginning of the test at the earliest, one sample was taken per test group for the particle size analysis (equipment: Stack Sampler Mark III (Andersen), vacuum compressed air pump (Millipore), sampling probe (internal diameter 6.9 mm), balance (Sartorius M3P and Mettler AE 240), evaluation unit (IBM-PC with software PGA).
Before the sampling, the impactor was equipped with glass-fiber collecting discs and a backup particle filter. The impactor was connected to the pump and the test apparatus, and one sample (9 L) was taken.
The impactor was taken apart, and the collecting discs and the backup particle filter were weighed.
The contents of the pre-impactor as well as the amounts of the material adsorbed on the walls of the impactor and in the sampling probe (wall losses) were also determined quantitatively.

- Temperature and humidity: the humidity in the inhalation system was not measured due to technical reasons. It is assumed that deviations of humidity values from the guideline requirements (especially low humidity in dust aerosol) did not influence the test results, because of the relative short exposure time.
The temperature in the inhalation system was measured continuously and recorded once.

TEST ATMOSPHERE
- Nominal concentration: the nominal concentration was calculated from the amount of substance consumed and the air flow.

- Brief description of analytical method used:gravimetric determination of the inhalation atmosphere concentration (apparatus: vacuum compressed air pump (Millipore), filtration equipment with probe (internal diameter: 4 mm, (Millipore)), filter (MN 85/90 Bf (d = 4.7 cm), sampling velocity 1.25 m/s, sampling amount 2 L, sampling frequency 1 sample about hourly)(balance: Mettler AT 250)
The preweighed filter was placed into the filtration equipment. By means of a vacuum compressed air pump a volume of the dust aerosol was drawn through the filter.
The dust concentration in mg/L was calculated from the difference between the preweight of the filter and the weight of the filter after sampling, with reference to the sample volume of the inhalation atmosphere. The concentrations were corrected for the amount of the added excipient.
- Samples taken from breathing zone: yes

VEHICLE
- Justification of choice of vehicle: the test substance was mixed with 1% (w/w) of aerosil in order to achieve a more uniform dust concentration in air.

TEST ATMOSPHERE (if not tabulated)
- MMAD* (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): MMAD: 5.1 µm (GSD: 2.4)(respirability**: 85 %)
Inspite of several technical measures (mixing, addition of some additives, use of cyclonic separator) no smaller particle size could be reached
* the amounts of the material determined in the particle size analysis were not corrected for the additive
** respirable dust fraction that might reach the alveolar region, obtained from the results of the particle size analysis
Analytical verification of test atmosphere concentrations:
yes
Remarks:
please refer "details on inhalation exposure" above
Duration of exposure:
4 h
Concentrations:
Actual concentration: 5.6 +/- 0.30 mg/L
Nominal concentration: 53.8 mg/L
No. of animals per sex per dose:
5 males / 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: the body weight of the animals was checked before the beginning of the test, after 7 days and at the end of the observation period. Clinical findings were recorded for each animal separately several times during exposure and at least once each workday in the observation period (no clinical observations were performed on test days 2, 3, 9 and 10 (holiday or weekend; day 0 = post-exposure on exposure day). A check for dead animals was made daily.
- Necropsy of survivors performed: yes, at the end of the 14-day observation period the animals were sacrificed with CO2 and were subjected to gross-pathological examination.
Statistics:
The statistical evaluation of the dose-response relationship was carried out using FORTRAN program AKPROZ. Depending on the data of the dose-response relationship obtained by way of experiment, this program is used to estimate the LC50 or to perform a Probit analysis (see Finney, D.J. (1971): "Probit Analysis", Cambridge University Press). Estimation of the LC50 will produce types LC50 greater, LC50 about, or LC50 smaller. If results are Type LC50 greater or LC50 smaller, an additional binominal test is carried out (Witting, H. (1974): "Mathematical Statistik", B.G. Teubner, Stuttgart, pp. 32 -35.), in order to verify these statements statistically, if necessary.
The calculation of the particle size distribution was carried out in the Deparment of Toxicology of BASF Aktiengesellschaft on the basis of mathematical methods for evaluating particle measurements (DIN 66141: Darstellung von Korngrößenverteilungen, DIN 66151: Partikelgrößenanalyse (Beuth-Vertrieb GmbH, D-W1000 Berlin 30 and D-W5000 Köln 1).
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.6 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: The statistical reliability is 99 %.
Mortality:
No mortality occurred at the limit concentration of 5.6 mg/L.
Clinical signs:
other:
Body weight:
Body weight gain was not affected over the whole post exposure period.
Gross pathology:
No pathological findings were noted in sacrificed animals.
Interpretation of results:
GHS criteria not met
Conclusions:
LC50 (male and female rats; 4 hours) > 5.6 mg/L
According to the EC-Regulation 1272/2008 and subsequent regulations, the test item is not classified as acute toxic via the inhalation route.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The study fulfils the requirements for acute inhalation toxicity under REACH (Regulation (EC) 1907/2006).

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute oral toxicity

One reliable study described in Kirsch (1992; OECD 401 (1987); GLP compliant) is considered to be reliable without restrictions and is used as key study for this endpoint. The LD50 was determined to be greater than 2200 mg/kg bw.

Acute inhalation toxicity

One reliable study described in Gamer (1992; OECD 403 (1981); GLP compliant) is considered to be reliable with restrictions and is used as key study for this endpoint. The LC50 was determined to be greater than 5.6 mg/L air (actual concentration).

Justification for classification or non-classification

Acute oral toxicity

Reference Kirsch (1992) will be used as key study for acute oral toxicity and will be used for classification.

The LD50 was determined to be greater than 2200 mg/kg bw. Thus, according to regulation (EC) 1272/2008 and subsequent amendments the substance is not classified.

Specific target organ toxicant (STOT) - single exposure: oral

The classification criteria according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – single exposure, oral are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value, oral for a Category 1 classification (C≤ 300 mg/kg bw) and at the guidance value, oral for a Category 2 classification (2000 mg/kg bw≥C > 300 mg/kg bw). No classification required.

Acute inhalation toxicity

The reference Gamer (1992) is considered as the key study for acute inhalation toxicity of zirconium iron pink zircon and will be used for classification. Male and female rats were exposed to 5.6 mg/L air (limit test, observation period 14 days) for 4 hours. No mortality occurred. The LC50 is > 5.6 mg/L air.

The classification criteria according to regulation (EC) 1272/2008 as acutely toxic are not met since the ATE is above 5.0 mg/L, hence no classification required.

Specific target organ toxicant (STOT) - single exposure: inhalation

The classification criteria according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – single exposure, inhalation (dust/mist/fume) are not met since no reversible or irreversible adverse health effects were observed immediately or delayed after exposure and no effects were observed at the guidance value, inhalation (dust/mist/fume) for a Category 1 classification (C≤ 1 mg/L/4h). Based on the outcome of the limit test on acute inhalation toxicity (0 animals of 10 animals died at a concentration of 5.6 mg/L/4h and no systemic or local effects were observed) it can safely be assumed that no classification for Category 2 (5.0 ≥C > 1.0 mg/L/4h) is required.